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Summary of the impact

The Million Women Study of 1.3 million UK women over the age of 50,
coordinated by the Cancer
Epidemiology Unit at Oxford, has established the relationship between
hormone replacement
therapy (HRT) and breast, endometrial, and ovarian cancer, and has had a
dramatic effect on HRT
prescription patterns and prescription guidelines worldwide. This has had
a major impact on
women's health. Prior to the study, one third of UK women aged 50-64 were
using HRT. The
marked decline in HRT use following publication of the study's findings
has led to a reduction in the
incidence of breast cancer among menopausal women.

Underpinning research

Clinicians have questioned the health impacts of hormone replacement
therapy (HRT) for decades.
Although originally touted as a wonder drug benefiting health, vitality
and femininity, HRT has been
plagued by fears of its relationship to cancer since the 1950s. At the
turn of the 21st Century these
fears were supported by a number of studies showing the correlation
between HRT and cancer, in
particularly the Women's Health Initiative (WHI) study, which took place
in the United States.

Initially dismissed in the United Kingdom, due to the WHI study not being
based on European
women's health, the need for a similar epidemiological study to reflect
the risk factors of HRT
among women in Europe became a high priority.

Setting out to understand the health impacts of HRT from a European
perspective, a team
coordinated by Professor Dame Valerie Beral of the University of Oxford's,
Cancer Epidemiology
Unit, began recruiting a large number of UK women to investigate how
reproductive history can
affect women's health — focusing particularly on hormone replacement
therapy.

The Million Women Study, launched in 1997, has since recruited 1.3
million UK women over the
age of 50, through NHS breast screening centres. It is the largest study
of its kind in the world [1],
with one in four UK women in the target age group participating.

Results of the study have been published in more than 50 papers since
1998 [2], primarily
examining the effect of HRT on the development of breast, endometrial and
ovarian cancer.

Breast Cancer: In a landmark paper published in 2003, the Million
Women Study showed that
women taking HRT were at an increased risk of developing breast cancer,
with an estimated
20,000 UK women aged 50-64 having potentially developed the disease due to
HRT use [3]. The
study also showed that the risk of side effects increased the longer a
woman used HRT, but
dropped to a normal level five years after the use of HRT had ceased.
Analyses in the Million
Women Study have also demonstrated that the effects of HRT vary
considerably by pattern of use
and tumour subtype [4].

Endometrial Cancer: In 2005 the Million Women Study confirmed that
post-menopausal women
who have not had a hysterectomy (and are taking oestrogen-only HRT), are
at an increased risk of
endometrial cancer [5]. The study also showed that the risk of endometrial
cancer increases in
women who take the HRT drug tibolone, but may be reduced in women taking
combined
oestrogen-progestogen HRT. Interestingly, they also found that these
effects were dependent on a
woman's body mass index, with cancer risk being greater in thinner women
than in those who were
obese [5], as had been observed for breast cancer risk [3].

Ovarian Cancer: Results of the Million Women Study published in
2007 showed that women taking
HRT were at a slightly higher risk of ovarian cancer [6]. The study
analysing 948,576 post-menopausal
women over five years found that for every 1,000 women taking HRT, 2.6
developed
ovarian cancer, compared to 2.2 in those not taking HRT [6].

[2]. The Million Women Study: Million Women Study. millionwomenstudy.org
athttp://www.millionwomenstudy.org/publications/ [Accessed 6/09/13].The
Million Women Study
website showing the number of publications that have resulted from the
Million Women
Study.

This research was funded by Cancer Research UK, the NHS Breast Screening
Programme and
the UK Medical Research Council.

Details of the impact

Results from the University of Oxford's Million Women Study, have changed
attitudes towards HRT
dramatically, leading to significant changes in public policy and HRT use
around the world. This
research has also led to significant reductions in breast cancer incidence
amongst menopausal
women.

Public Policy
Results from the Million Women Study have influenced a number of European
health agency
guidelines, which now recommend that women at a high risk of breast cancer
consider alternative
options to HRT. These agencies include the Royal College of Obstetricians
and Gynaecologists
[A], the Medicines and Healthcare products Regulatory Agency [B], and the
European Medicines
Agency [C].

Culture and Behaviour
Since publication, the Million Women Study has been presented to the
public at length both in print
and online — from articles in the New York Times and Daily
Telegraph to women's health blogs and
cancer charity websites around the world.

This far-reaching public awareness of the study and its findings led to
significant behavioural
changes, predominately resulting in the swift decline of HRT prescriptions
throughout Europe and
the US from 2003. In stark contrast to the increase in HRT prescriptions
between 1991 and 1996,
which remained stable through to 2001, sales of HRT fell by 50% between
2002 and 2005
following the publication of the WHI trial and the Million Women Study
[D]. Recent studies
demonstrate the continuing impact of this research on behaviour in terms
of continued reduced
HRT use [E, F].

One such study published in 2010 in Belgium (a country known to have one
of the highest
incidences of breast cancer in Europe), shows that the proportion of women
aged 50-69 years
using HRT in Flanders went from a 20% peak in 2001, to just 8% in 2008.
The study also showed
a decrease in breast cancer incidence [G].

Health
Due to the substantial decline in the use of HRT in many countries, the
incidence of breast cancer
has markedly decreased in women between the ages of 45 and 64. Declines in
the rate of breast
cancer have been strongest for women between the age of 50 and 60 years,
with rates which were
previously on the incline dropping by 0.8% a year [H, I]. More recent data
[E, F, I], which were
published between 2010 and 2012, show that lower levels of HRT use and
breast cancer incidence
subsequent to the steep decline in HRT use, which followed the publication
of the Million Women
Study, have continued into the REF assessment period of 2008 - 2013.
Breast cancer incidence in
Great Britain among women aged 50 to 64 peaked in 2004 and then showed a
rapid decline over
three years, with the lower rates then persisting through to at least 2010
(the most recently
available incidence data) and being partly attributed to the reduction in
HRT use in this age group
[I]. Similarly, a report assessing breast cancer incidence in Belgium up
to the end of 2008 showed
a significant drop in breast cancer incidence, which was attributed to the
significant decrease in
HRT use in Belgium during and leading up 2008 [F].

Sources to corroborate the impact

[A]. Whitehead, M. I. RCOG study group on menopause and HRT RCOG
recommendations on
hormone replacement therapy. Lancet 365, 749 (2005). PubMed ID:
15733708.Paper making Royal College of Obstetricians and Gynaecologists
recommendations on
HRT use for menopausal women, which although published in 2005 has not
been
superseded.

[B]. Further advice on safety of hormone replacement therapy (HRT), athttp://www.mhra.gov.uk/NewsCentre/Pressreleases/CON002044 [Accessed
6/09/13].Recommendations from the Medicines and Healthcare products
Regulatory Agency (UK) on
HRT use, which refers directly to the Million Women Study.